ABSTRACT Project 1 (Peter J. Gianaros, PL) Stress, Emotion, and Neural Circuits for CVD Risk Project 1 (P1) aims to identify features of visceral control circuits of the brain (brain phenotypes) that account for the influence of stress- and emotion-related processes on physiological mediators of cardiovascular disease (CVD) risk in midlife. P1 has a specific focus on indicators of autonomic cardiovascular control, glucocorticoid regulation, stressor-evoked cardiovascular reactivity, and systemic inflammation. We posit that individual differences in the expression of these mediators of CVD risk will be explained in part by multivariate classes of brain phenotypes derived from: (i) fMRI activation and connectivity changes evoked by a standardized battery of psychological-stressor and emotion-processing and regulation tasks; (ii) intrinsic functional network connectivity metrics derived from resting-state fMRI; as well as (iii) structural metrics of white matter fascicles that enable communication within visceral control circuits. A second objective is to test whether brain phenotypes for visceral control predict the multiyear progression of preclinical markers of vascular disease and dysfunction, as reflected by carotid artery morphology, arterial stiffness, and endothelium dependent vasodilation. A third objective is to test whether multi-system physiological mediators of CVD risk account for the prospective associations between brain phenotypes for visceral control and the progression of preclinical markers of vascular disease and dysfunction. Finally, we test whether the latter prospective associations depend on a known cardio-protective health behavior that may modify visceral control circuits, as well as stress and emotion processes; namely, physical activity. To these ends, we propose a 8.5-to-11 yr follow-up of systemic physiological mediators and markers of preclinical CVD in 360 men and women from two study cohorts ? the AHAB2 and PIP cohorts ? established by unique NHLBI-supported neuroscience studies of CVD risk in midlife. We also seek to recruit and longitudinally follow for 32 months a de novo sample of 350 midlife adults who will complete similar and expanded assessment batteries as implemented in AHAB2 and PIP, including detailed assessments of brain function and structure, biological, behavioral, and socio-demographic risk factors for CVD, as well as markers of preclinical vascular disease and dysfunction. In synergy with the other projects of this P01, P1 affords novel tests of whether individual differences in risk for CVD are partly explained or modified by brain phenotypes for visceral control. If so, this work will advance our understanding of the human neural substrates for biological and behavioral influences on the development of CVD.